Purpose Mesopancreas resection is a crucial but difficult procedure when performing pancreaticoduodenectomy. This study evaluated the influence of mesopancreas thickness on surgical outcomes in patients undergoing pancreaticoduodenectomy. Methods We measured the thickness of the fat tissue on the right side of the superior mesenteric artery from the dorsal margin of the confluence of the superior mesenteric vein and portal vein to the ventral margin of the left renal vein on preoperative contrast-enhanced computed tomography and defined it as the mesopancreas thickness. We evaluated the correlation between mesopancreas thickness and intraoperative and postoperative variables in 357 patients who underwent pancreaticoduodenectomy. Results Multivariate analysis revealed that a thick mesopancreas was significantly associated with a long operative time (β = 10.361; 95% confidence interval, 0.370–20.353, p = 0.042), high estimated blood loss (β = 36.038; 95% confidence interval, -27.192–99.268, p = 0.013), and a low number of resected lymph nodes (β = -1.551; 95% confidence interval, -2.662–-0.439, p = 0.006). This analysis further revealed that thick mesopancreas was a significant risk factor for overall morbidity (odds ratio 2.170; 95% confidence interval 1.340–3.520, p = 0.002), major morbidity (odds ratio 2.430; 95% confidence interval 1.360–4.340, p = 0.003), and a longer hospital stay (β = 2.386; 95% confidence interval 0.299–4.474, p = 0.025). Conclusion A thick mesopancreas could predict a longer operation time, higher estimated blood loss, fewer resected lymph nodes, more frequent overall and major morbidities, and a longer hospital stay in patients who underwent pancreaticoduodenectomy more precisely than the body mass index.